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    Small Molecule Antineoplastic FMS-like Tyrosine Kinase-3 (FLT-3) Inhibitors

    BOXED WARNING

    Differentiation syndrome

    Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with gilteritinib therapy; this syndrome may be life-threatening or fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as fever, dyspnea, hypoxia, pulmonary infiltrates, pulmonary edema, pleural or pericardial effusion, rapid weight gain or peripheral edema, rash, hypotension, or renal dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or PO/IV equivalent) and closely monitor hemodynamic parameters until improvement. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt gilteritinib therapy if severe signs or symptoms persist after 48 hours of corticosteroid therapy. Resume gilteritinib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Differentiation syndrome may occur as soon as 2 days and up to 75 days after starting gilteritinib.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral tyrosine kinase inhibitor
    Used for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia that is FLT3 mutation-positive
    Differentiation syndrome has been reported

    COMMON BRAND NAMES

    XOSPATA

    HOW SUPPLIED

    XOSPATA Oral Tab: 40mg

    DOSAGE & INDICATIONS

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: Gilteritinib has been designated an orphan drug by the FDA for the treatment of AML.
    For the treatment of relapsed or refractory FLT3 mutation-positive AML.
    Oral dosage
    Adults

    120 mg orally once daily. Continue therapy for a minimum of 6 cycles in patients who do not have unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity. At a median follow-up, 17.8 months (range, 14.9 to 19.1 months), the median overall survival (OS) time was significantly improved in adult patients with relapsed or refractory FLT3-mutated AML who received gilteritinib compared with chemotherapy (9.3 months vs. 5.6 months; hazard ratio (HR) = 0.64; 95% CI, 0.49 to 0.83; p = 0.0004) in a multicenter, randomized (2:1), phase 3 trial (n = 371; the ADMIRAL trial). Chemotherapy consisted or high-intensity therapy with mitoxantrone, etoposide, and cytarabine (MEC; n = 33) or granulocyte colony-stimulating factor, fludarabine, cytarabine, and idarubicin (FLAG-IDA; n = 42) or low-intensity therapy with low-dose cytarabine (n = 17) or azacitidine (n = 32). In a subgroup analysis, OS was also significantly improved in patients who received gilteritinib compared with either high-intensity (HR = 0.66; 95% CI, 0.47 to 0.93) or low-intensity (HR = 0.56; 95% CI, 0.38 to 0.84) chemotherapy [63787]

    MAXIMUM DOSAGE

    Adults

    120 mg/day PO.

    Geriatric

    120 mg/day PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment are not available; it appears that no initial dosage adjustments are needed. Gilteritinib has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C).[63787]

    Renal Impairment

    Specific guidelines for dosage adjustments in mild (creatinine clearance (CrCl) of 50 to 80 mL/min) or moderate (CrCl of 30 to 50 mL/min) renal impairment are not available; it appears that no initial dosage adjustments are needed. Gilteritinib has not been evaluated in patients with severe renal impairment (CrCl of 29 mL/min or less).[63787]

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Do not break or crush gilteritinib tablets; swallow whole with a whole cup of water.
    Take with or without food.
    Take orally about the same time each day. If a dose is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the next day.
    Do not administer 2 doses within 12 hours.[63787]

    STORAGE

    XOSPATA:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Differentiation syndrome

    Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with gilteritinib therapy; this syndrome may be life-threatening or fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as fever, dyspnea, hypoxia, pulmonary infiltrates, pulmonary edema, pleural or pericardial effusion, rapid weight gain or peripheral edema, rash, hypotension, or renal dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or PO/IV equivalent) and closely monitor hemodynamic parameters until improvement. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt gilteritinib therapy if severe signs or symptoms persist after 48 hours of corticosteroid therapy. Resume gilteritinib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Differentiation syndrome may occur as soon as 2 days and up to 75 days after starting gilteritinib.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, electrolyte imbalance, females, geriatric, heart failure, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    QT prolongation has been reported with gilteritinib therapy. Therapy interruption and a dose reduction are necessary in patients who develop a QTc interval greater than 500 milliseconds. Obtain an ECG prior to starting gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of cycles 2 and 3. Monitor electrolytes (e.g., potassium and magnesium levels) prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy. Correct electrolyte imbalance prior to and during treatment with gilteritinib.[63787] Use gilteritinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, and patients with diabetes mellitus, thyroid disease, malnutrition, or alcoholism may also be at increased risk for QT prolongation.[28432] [28457] [56959] [56961] [56592] [63787]

    Arthralgia

    Muscle symptoms such as myalgia and arthralgia may occur with gilteritinib use. Monitor serum creatine phosphokinase (CPK) levels prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy.

    Renal impairment

    Renal impairment has been reported with gilteritinib therapy. Monitor blood chemistries (e.g., renal function tests) prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy. [63787]

    Hepatic disease

    Hepatotoxicity has been reported with gilteritinib therapy. Monitor blood chemistries (e.g., liver function tests) prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy. Patient with hepatic disease may be at increased risk for QT prolongation.[63787]

    Pregnancy

    Gilteritinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking gilteritinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although gilteritinib has not been evaluated in pregnant women, fetal toxicity occurred when pregnant rats received a gilteritinib dose resulting in approximately 0.4-times the exposure that was observed in humans who received the recommended dose. Fetal toxicity in this animal study included embryo-fetal death; decreased fetal body and placental weight; decreased numbers of ossified sternebrae and sacral and caudal vertebrae; and an increased incidence of fetal gross external (e.g., anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (e.g., microphthalmia, atrial and/or ventricular defects, malformed/absent kidney, and malpositioned adrenal gland and ovary), and skeletal (e.g., sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities.[63787]

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during gilteritinib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for at least 6 months after the final gilteritinib dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception to avoid potential drug exposure in female partners of reproductive potential during therapy and for at least 4 months after the final gilteritinib dose.

    Breast-feeding

    It is not known if gilteritinib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from gilteritinib, women should be advised against breast-feeding during gilteritinib therapy and for at least 2 months after the last dose.[63787]

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 21.0-21.0
    hypophosphatemia / Delayed / 14.0-14.0
    hyponatremia / Delayed / 12.0-12.0
    dyspnea / Early / 12.0-12.0
    myalgia / Early / 7.0-7.0
    arthralgia / Delayed / 7.0-7.0
    oral ulceration / Delayed / 0-7.0
    hypotension / Rapid / 7.0-7.0
    hypocalcemia / Delayed / 6.0-6.0
    hypertriglyceridemia / Delayed / 6.0-6.0
    fatigue / Early / 6.0-6.0
    malaise / Early / 6.0-6.0
    pancreatitis / Delayed / 4.0-4.0
    pericardial effusion / Delayed / 0-4.0
    heart failure / Delayed / 4.0-4.0
    erythema / Early / 0-3.0
    differentiation syndrome / Delayed / 3.0-3.0
    myocarditis / Delayed / 0-2.0
    pericarditis / Delayed / 0-2.0
    rash / Early / 0-1.2
    GI perforation / Delayed / 0-1.0
    cardiac arrest / Early / 0-1.0
    cough / Delayed / 0-1.0
    fever / Early / 0-0.8
    constipation / Delayed / 0-0.4
    edema / Delayed / 0-0.4
    peptic ulcer / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known

    Moderate

    peripheral neuropathy / Delayed / 18.0-18.0
    QT prolongation / Rapid / 1.0-9.0
    encephalopathy / Delayed / 1.0-1.0
    colitis / Delayed / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 11.0-11.0
    muscle cramps / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    hyperkeratosis / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    leukocytosis / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aclidinium; Formoterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and alfuzosin is necessary. Gilteritinib has been associated with QT prolongation. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and gilteritinib. Monitor for QT prolongation if concurrent use is necessary. Gilteritinib has been associated with QT prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Anagrelide: (Major) Do not use anagrelide with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apalutamide: (Major) Avoid coadministration of gilteritinib and apalutamide due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; apalutamide is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Apomorphine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and apomorphine is necessary as concurrent use may increase the risk of QT prolongation. Gilteritinib has been associated with QT prolongation. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and aripiprazole is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with gilteritinib; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Gilteritinib has been associated with QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid concomitant use of artemether; lumefantrine with gilteritinib due to the potential for additive QT prolongation. Consider ECG monitoring if gilteritinib must be used with or after artemether; lumefantrine treatment. Both artemether; lumefantrine and gilteritinib have been associated with QT prolongation.
    Asenapine: (Major) Avoid concomitant use of asenapine with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Atazanavir: (Major) Consider an alternative to atazanavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Atazanavir; Cobicistat: (Major) Consider an alternative to atazanavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Atomoxetine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and atomoxetine is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of gilteritinib and phenobarbital due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenobarbital is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Azithromycin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and azithromycin is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and bedaquiline is necessary. Both drugs have been associated with QT prolongation. Coadministration may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of gilteritinib and phenobarbital due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenobarbital is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and metronidazole is necessary. Gilteritinib has been associated with QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and metronidazole is necessary. Gilteritinib has been associated with QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and buprenorphine is necessary. FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. Gilteritinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and buprenorphine is necessary. FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. Gilteritinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Carbamazepine: (Major) Avoid coadministration of gilteritinib and carbamazepine due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; carbamazepine is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Ceritinib: (Major) Consider an alternative to ceritinib during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, monitor for gilteritinib-related adverse reactions as well as monitoring periodic ECGs and serum electrolytes. Interrupt therapy, dose reduce, or discontinue treatment if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. In addition, both drugs have been associated with QT prolongation.
    Chloramphenicol: (Major) Consider an alternative to chloramphenicol during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Chloroquine: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and chloroquine is necessary. Gilteritinib has been associated with QT prolongation. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpromazine: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and chlorpromazine is necessary. Gilteritinib has been associated with QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ciprofloxacin is necessary. Gilteritinib has been associated with QT prolongation. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Use of gilteritinib with cisapride is contraindicated because of the potential for torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Gilteritinib has been associated with QT prolongation.
    Citalopram: (Major) Avoid coadministration of citalopram with gilteritinib due to the potential for decreased response to citalopram and an additive risk of QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like citalopram that target these receptors. In addition, both drugs have been associated with QT prolongation.
    Clarithromycin: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Clofazimine: (Major) Use caution and monitor electrocardiograms (ECGs) for evidence of QT prolongation if concurrent use of gilteritinib and clofazimine is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and clozapine is necessary. Gilteritinib has been associated with QT prolongation. Clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Coadministration has the potential for additive QT prolongation.
    Cobicistat: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Codeine; Phenylephrine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Codeine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Conivaptan: (Major) Consider an alternative to conivaptan during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Crizotinib: (Major) Avoid coadministration of crizotinib with gilteritinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
    Darunavir: (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Darunavir; Cobicistat: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Dasatinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and dasatinib is necessary. Gilteritinib has been associated with QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Coadministration has the potential for additive QT prolongation.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving gilteritinib and degarelix as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Gilteritinib has been associated with QT prolongation.
    Delavirdine: (Major) Consider an alternative to delavirdine during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Desflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Desipramine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and deutetrabenazine is necessary. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the deutetrabenazine dosage. Clinically relevant QTc prolongation may occur with deutetrabenazine. Gilteritinib has also been associated with QT prolongation.
    Dextromethorphan; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Dextromethorphan; Quinidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and quinidine is necessary. Gilteritinib has been associated with QT prolongation. Quinidine is associated with QT prolongation and torsade de pointes (TdP).
    Disopyramide: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and disopyramide is necessary. Gilteritinib has been associated with QT prolongation. Disopyramide has been associated with QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive QT prolongation.
    Dofetilide: (Major) Coadministration of dofetilide and gilteritinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation.
    Dolasetron: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and dolasetron is necessary. Gilteritinib has been associated with QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Coadministration has the potential for additive QT prolongation.
    Dolutegravir; Rilpivirine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and donepezil is necessary. Coadministration has the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Donepezil; Memantine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and donepezil is necessary. Coadministration has the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Doxepin: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Severe) Use of gilteritinib with dronedarone is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Dronedarone is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Do not use droperidol and gilteritinib together due to the potential for additive QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Gilteritinib has also been associated with QT prolongation.
    Efavirenz: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Eliglustat: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and eliglustat is necessary. Gilteritinib has been associated with QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and gilteritinib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
    Enflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Entrectinib: (Major) Avoid coadministration of entrectinib with gilteritinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Both entrectinib and gilteritinib have been associated with QT prolongation.
    Eribulin: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and eribulin is necessary. ECG monitoring is recommended. Gilteritinib and eribulin have both been associated with QT prolongation.
    Erythromycin: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and erythromcyin is necessary. Gilteritinib has been associated with QT prolongation. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive cardiotoxicity.
    Erythromycin; Sulfisoxazole: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and erythromcyin is necessary. Gilteritinib has been associated with QT prolongation. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive cardiotoxicity.
    Escitalopram: (Major) Avoid coadministration of escitalopram with gilteritinib if possible due to the potential for decreased response to escitalopram and additive QT prolongation. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like escitalopram that target these receptors. In addition, both drug have been associated with QT prolongation.
    Ezogabine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and ezogabine is necessary. Both drugs have been associated with QT prolongation; coadministration has the potential for additive effects.
    Fingolimod: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and fingolimod is necessary. Gilteritinib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and flecainide is necessary. Gilteritinib has been associated with QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as gilteritinib, is contraindicated. Both drugs have been associated with QT prolongation.
    Fluoxetine: (Major) Avoid coadministration of fluoxetine with gilteritinib if possible due to the potential for additive QT prolongation and decreased response to fluoxetine. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration has the potential for additive cardiotoxicity. Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluoxetine that target these receptors.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of fluoxetine with gilteritinib if possible due to the potential for additive QT prolongation and decreased response to fluoxetine. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration has the potential for additive cardiotoxicity. Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluoxetine that target these receptors. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and fluphenazine is necessary. Gilteritinib has been associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine with gilteritinib if possible due to the potential for decreased response to fluvoxamine and additive QT prolongation. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluvoxamine that target these receptors. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
    Formoterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Consider an alternative to fosamprenavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Foscarnet: (Major) Avoid concomitant use of foscarnet with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of gilteritinib and fosphenytoin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; fosphenytoin is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Gemifloxacin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and gemifloxacin is necessary. Gilteritinib has been associated with QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours after oral administration of gemifloxacin and may be dose-dependent.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and gilteritinib together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Gilteritinib has been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with gilteritinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Gilteritinib has been associated with QT prolongation.
    Glycopyrrolate; Formoterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and goserelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Granisetron: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and granisetron is necessary. Both drugs have been associated with QT prolongation.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice due to increased gilteritinib exposure resulting in treatment-related adverse events. Gilteritinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Halogenated Anesthetics: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Haloperidol: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and haloperidol is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Histrelin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and histrelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Hydroxychloroquine: (Major) Do not administer hydroxychloroquine and gilteritinib together due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation; coadministration has the potential for additive effects.
    Hydroxyzine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and hydroxyzine is necessary. Gilteritinib has been associated with QT prolongation. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive QT effects.
    Ibutilide: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and ibutilide is necessary. Gilteritinib has been associated with QT prolongation. Ibutilide can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Consider an alternative to idelalisib during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Iloperidone: (Major) Avoid concomitant use of iloperidone with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation; coadministration has the potential for additive effects.
    Imipramine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Major) Consider an alternative to indinavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with gilteritinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment. Both drugs have been associated with QT prolongation.
    Isoflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of gilteritinib and rifampin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; rifampin is a combined P-gp and strong CYP3A4 inducer. Coadministration with rifampin decreased the gilteritinib AUC by 70% in a drug interaction study
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of gilteritinib and rifampin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; rifampin is a combined P-gp and strong CYP3A4 inducer. Coadministration with rifampin decreased the gilteritinib AUC by 70% in a drug interaction study
    Itraconazole: (Major) Consider an alternative to itraconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with gilteritinib if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Gilteritinib has also been associated with QT prolongation.
    Ketoconazole: (Major) Consider an alternative to ketoconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with gilteritinib is necessary; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Gilteritinib has been associated with QT prolongation. Coadministration has the potential for additive effects.
    Lefamulin: (Major) Avoid coadministration of lefamulin with gilteritinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Gilteritinib has been associated with QT prolongation.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Letermovir: (Moderate) Consider an alternative to letermovir in patients also receiving cyclosporine during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration of all 3 drugs is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor; however, when administered with cyclosporine the effect may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Leuprolide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and leuprolide is necessary as concurrent use may increase the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Leuprolide; Norethindrone: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and leuprolide is necessary as concurrent use may increase the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Levalbuterol: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and levofloxacin is necessary. Gilteritinib has been associated with QT prolongation. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and lithium is necessary. Both drugs have been associated with QT prolongation.
    Lofexidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and lofexidine is necessary. Monitor ECG. Both drugs have been associated with QT prolongation.
    Long-acting beta-agonists: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and loperamide is necessary. Gilteritinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and loperamide is necessary. Gilteritinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Consider an alternative to lopinavir; ritonavir during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation. (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of gilteritinib and lumacaftor; ivacaftor due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; lumacaftor; ivacaftor is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of gilteritinib and lumacaftor; ivacaftor due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; lumacaftor; ivacaftor is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Macimorelin: (Major) Avoid concomitant use of macimorelin with gilteritinib due to the potential for additive QT prolongation. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended.
    Maprotiline: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and maprotiline is necessary. Gilteritinib has been associated with QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Mefloquine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and mefloquine is necessary. Gilteritinib has been associated with QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Metaproterenol: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Use extreme caution and monitor for additive QT prolongation if concurrent use of gilteritinib and methadone is necessary; carefully assess treatment risks versus benefits. Gilteritinib has been associated with QT prolongation. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and metronidazole is necessary. Gilteritinib has been associated with QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and midostaurin is necessary. Consider obtaining periodic electrocardiograms. Both drugs have been associated with QT prolongation.
    Mifepristone: (Major) Consider an alternative to mifepristone during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mirtazapine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and mirtazapine is necessary. Gilteritinib has been associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Moxifloxacin: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and moxifloxacin is necessary. Gilteritinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nefazodone: (Major) Consider an alternative to nefazodone during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Nelfinavir: (Major) Consider an alternative to nelfinavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Nilotinib: (Major) Avoid concomitant use of nilotinib with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
    Norfloxacin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and norfloxacin is necessary. Gilteritinib has been associated with QT prolongation. Quinolones have been associated with risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and octreotide is necessary. Gilteritinib has been associated with QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Until further data are available, it is suggested to use octreotide cautiously in patients receiving drugs which prolong the QT interval.
    Ofloxacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ofloxacin is necessary. Gilteritinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Ondansetron: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ondansetron is necessary. ECG monitoring is recommended. Gilteritinib has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osimertinib: (Major) Avoid coadministration of gilteritinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Gilteritinib has also been associated with QT prolongation.
    Oxaliplatin: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and oxaliplatin is necessary. Monitor ECGs and electrolytes periodically; correct electrolyte abnormalities prior to administration of oxaliplatin. Gilteritinib has been associated with QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Avoid concomitant use of paliperidone with gilteritinib due to the potential for additive QT prolongation. If coadministration is necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Both paliperidone and gilteritinib have been associated with QT prolongation. Torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose.
    Panobinostat: (Major) Coadministration of panobinostat and gilteritinib is not recommended. Both drugs have been associated with QT prolongation.
    Paroxetine: (Major) Avoid coadministration of paroxetine with gilteritinib if possible due to the potential for decreased response to paroxetine. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like paroxetine that target these receptors.
    Pasireotide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and pasireotide is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Concomitant use of pazopanib with gilteritinib is not advised due to the potential for additive QT prolongation. If use together is necessary, closely monitor the patient.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and pentamidine is necessary. Gilteritinib and systemic pentamidine have both been associated with QT prolongation.
    Perphenazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and perphenazine is necessary. Gilteritinib has been associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and perphenazine is necessary. Gilteritinib has been associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid coadministration of gilteritinib and phenobarbital due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenobarbital is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Phenylephrine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Phenytoin: (Major) Avoid coadministration of gilteritinib and phenytoin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenytoin is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Pimavanserin: (Major) Avoid concomitant use of pimavanserin with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Pimozide: (Severe) Use of gilteritinib with pimozide is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Pimozide is associated with a well-established risk of QT prolongation and TdP.
    Pirbuterol: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with gilteritinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Gilteritinib has also been associated with QT prolongation.
    Posaconazole: (Major) Consider an alternative to posaconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Primaquine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and primaquine is necessary. Both drugs have been associated with QT prolongation.
    Primidone: (Major) Avoid coadministration of gilteritinib and primidone due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; primidone is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Procainamide: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and procainamide is necessary. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Gilteritinib has also been associated with QT prolongation.
    Prochlorperazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and prochlorperazine is necessary. Gilteritinib has been associated with QT prolongation. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Propafenone: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and propafenone is necessary. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Gilteritinib has also been associated with QT prolongation.
    Protriptyline: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid concomitant use of quetiapine with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and quinidine is necessary. Gilteritinib has been associated with QT prolongation. Quinidine is associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid concomitant use of quinine with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ranolazine is necessary. Gilteritinib has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Ribociclib: (Major) Avoid coadministration of ribociclib with gilteritinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Gilteritinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with gilteritinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Gilteritinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Major) Avoid coadministration of gilteritinib and rifampin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; rifampin is a combined P-gp and strong CYP3A4 inducer. Coadministration with rifampin decreased the gilteritinib AUC by 70% in a drug interaction study
    Rilpivirine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Moderate) Use caution and closely monitor for additive QT prolongation if concurrent use of gilteritinib and risperidone is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) during risperidone therapy have primarily occurred in the overdosage setting.
    Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Romidepsin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and romidepsin is necessary. Consider monitoring of electrolytes and ECGs at baseline and periodically during treatment. Both drugs have been associated with QT prolongation.
    Salmeterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Severe) Coadministration of gilteritinib and saquinavir is contraindicated due to the risk of additive QT prolongation and other gilteritinib-related toxicities. Gilteritinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Gilteritinib has been associated with QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias.
    Sertraline: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and sertraline is necessary. Gilteritinib has been associated with QT prolongation. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Short-acting beta-agonists: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving gilteritinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Gilteritinib has also been associated with QT prolongation.
    Solifenacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and solifenacin is necessary. Gilteritinib has been associated with QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with gilteritinib is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs have been associated with QT prolongation.
    Sotalol: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and sotalol is necessary. Gilteritinib has been associated with QT prolongation. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of gilteritinib and St. John's Wort due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; St. John's Wort is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Sunitinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and sunitinib is necessary. Both drugs have been associated with QT prolongation.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with gilteritinib. Gilteritinib has been associated with QT prolongation. Tacrolimus may also prolong the QT interval and cause torsade de pointes.
    Tamoxifen: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tamoxifen is necessary. Gilteritinib has been associated with QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and telavancin is necessary. Both drugs have been associated with QT prolongation.
    Telithromycin: (Major) Consider an alternative to telithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Terbutaline: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a short-acting beta-agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid concomitant use of tetrabenazine with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
    Thioridazine: (Severe) Use of gilteritinib with thioridazine is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Thioridazine is associated with a well-established risk of QT prolongation and TdP.
    Tiotropium; Olodaterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Consider an alternative to tipranavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Tolterodine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tolterodine is necessary. Gilteritinib has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Avoid coadministration of gilteritinib with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Gilteritinib has also been associated with QT prolongation.
    Trazodone: (Major) Avoid concomitant use of trazodone with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Tricyclic antidepressants: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and trifluoperazine is necessary. Gilteritinib has been associated with QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimipramine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triprolidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tripolidine is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Triptorelin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and triptorelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Umeclidinium; Vilanterol: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a long-acting beta agonist is necessary. Gilteritinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with gilteritinib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Gilteritinib has also been associated with QT prolongation.
    Vardenafil: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vardenafil is necessary. Gilteritinib has been associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vemurafenib is necessary. ECG monitoring is recommended. Both drugs have been associated with QT prolongation.
    Venlafaxine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and venlafaxine is necessary. Gilteritinib has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Voriconazole: (Major) Consider an alternative to voriconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Vorinostat: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vorinostat is necessary. Both drugs have been associated with QT prolongation.
    Ziprasidone: (Major) Avoid concomitant use of ziprasidone with gilteritinib due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Gilteritinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking gilteritinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although gilteritinib has not been evaluated in pregnant women, fetal toxicity occurred when pregnant rats received a gilteritinib dose resulting in approximately 0.4-times the exposure that was observed in humans who received the recommended dose. Fetal toxicity in this animal study included embryo-fetal death; decreased fetal body and placental weight; decreased numbers of ossified sternebrae and sacral and caudal vertebrae; and an increased incidence of fetal gross external (e.g., anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (e.g., microphthalmia, atrial and/or ventricular defects, malformed/absent kidney, and malpositioned adrenal gland and ovary), and skeletal (e.g., sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities.[63787]

    Counsel patients about the reproductive risk and contraception requirements during gilteritinib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for at least 6 months after the final gilteritinib dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception to avoid potential drug exposure in female partners of reproductive potential during therapy and for at least 4 months after the final gilteritinib dose.

    MECHANISM OF ACTION

    Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). It demonstrates the ability to inhibit FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, tyrosine kinase domain (TKD) mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induces apoptosis in leukemic cells expressing FLT3-ITD. In patients with relapsed or refractory AML administered gilteritinib, substantial (greater than 90%) inhibition of FLT3 phosphorylation was rapid (within 24 hours after the first dose) and sustained, as characterized by an ex vivo plasma inhibitor activity (PIA) assay.[63787]
     
    Gilteritinib inhibits 5-Hydroxytryptamine receptor 2B (5HT2B), also known as serotonin receptor 2B, and sigma nonspecific receptors in vitro. Concomitant use of gilteritinib may reduce the effects of drugs that target these receptors.[63787]

    PHARMACOKINETICS

    Gilteritinib is administered orally. It is approximately 94% bound to human plasma proteins in vivo and is primarily bound to human serum albumin in vitro. The population mean (%CV) estimates of apparent central and peripheral volume of distribution is 1,092 L (9.22%) and 1,100 L (4.99%), respectively, which may indicate extensive tissue distribution. Gilteritinib is primarily metabolized via CYP3A4 in vitro. At steady state, the primary metabolites in humans include M17 (formed via N-dealkylation and oxidation), M16 (formed via N-dealkylation), and M10 (formed via N-dealkylation); however, none of these 3 metabolites exceed 10% of overall parent exposure. Single radiolabeled dose studies show 64.5% of the total administered gilteritinib dose is excreted in the feces. Of the total radiolabeled dose, 16.4% was recovered in the urine as unchanged drug and metabolites. The estimated half-life is 113 hours and the estimated apparent clearance is 14.85 L/h.[63787]
     
     
    Affected cytochrome P450 isoenzymes and drug transporters, and other receptors: CYP3A4, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT) 1
    Gilteritinib is a CYP3A4 and P-glycoprotein (P-gp) substrate. After coadministration with a combined P-gp and strong CYP3A inducer, the gilteritinib Cmax decreased by approximately 30% and the AUC decreased by approximately 70%. After coadministration with a strong CYP3A inhibitor, the gilteritinib Cmax increased by approximately 20% and the AUC increased by approximately 120%. After coadministration with a moderate CYP3A inhibitor, the gilteritinib Cmax increased by approximately 16% and the AUC increased by approximately 40%. Gilteritinib increased the Cmax and AUC of a CYP3A substrate by approximately 10% when coadministered. Gilteritinib decreased the Cmax and AUC of a multidrug and toxin extrusion (MATE) 1 substrate by less than 10% when coadministered. Gilteritinib also has the potential to inhibit breast cancer resistance protein (BCRP) and organic cation transporter (OCT) 1.[63787]

    Oral Route

    The time to maximum gilteritinib concentration (Tmax) is approximately between 4 and 6 hours after the dose in the fasted state. Gilteritinib exposure (Cmax and AUC) increases proportionally with once daily doses ranging from 20 mg to 450 mg (0.27 to 3.75 times the recommended dose). The mean steady-state Cmax is 374 ng/mL and AUC is 6943 ng x h/mL. Steady-state plasma concentrations are reached within 15 days of dosing with an approximate 10-fold accumulation.[63787]
     
    Effects of food: In healthy adults administered a single 40 mg gilteritinib dose (0.3 times the recommended dose), the Cmax decreased by 26% and the AUC decreased by less than 10% when coadministered with a high-fat meal (approximately 800 to 1000 calories with 500 to 600 fat calories) compared to a fasted state. The median Tmax was delayed 2 hours when administered with a high-fat meal.[63787]